Certain substituted ureas, as modulators of kinase activity

ABSTRACT

Certain chemical entities chosen from compounds of Formula 1 and pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, and prodrugs thereof, are provided herein. Pharmaceutical compositions comprising at least one chemical entity and one or more pharmaceutically acceptable vehicles chosen from carriers, adjuvants, and excipients, are also provided herein. Methods of treating patients suffering from certain diseases and disorders responsive to angiogenic kinase modulation, which comprise administering to such patients an amount of at least one chemical entity effective to reduce signs or symptoms of the disease or disorder are disclosed. These diseases include cancer, including breast neoplasia, endometrial cancer, colon cancer, and neck squamous cell carcinoma. Methods of treatment include administering at least one chemical entity as a single active agent or administering such at least one chemical entity in combination with one or more other therapeutic agents. A method for determining the presence or absence of an angiogenic kinase in a sample comprising contacting the sample with at least one chemical entity under conditions that permit detection of activity of the angiogenic kinase, detecting a level of the activity of the angiogenic kinase, and therefrom determining the presence or absence of the angiogenic kinase in the sample.

This application claims priority to U.S. Application No. 60/677,758,filed May 3, 2005; and Application No. 60/677,530, filed May 3, 2005,each of which is incorporated herein by reference.

Provided herein are certain substituted ureas and related compounds,compositions comprising such compounds, and methods of their use.

Protein kinases, the largest family of human enzymes, encompass wellover 500 proteins. Kinases play a key role in angiogenesis.Angiogenesis, the formation of new blood vessels from preexisting ones,plays a significant role in many pathological settings, includingcancer, chronic inflammation, diabetic retinopathy, psoriasis,rheumatoid arthritis, and macular degeneration. Anti-angiogenic therapyrepresents a potentially important approach for the treatment of solidtumors and other diseases associated with dysregulated vascularization.

The process of angiogenesis is complex, requiring the concerted actionsof multiple angiogenic mediators as well as the participation ofdifferent cell types. Key angiogenesis mediators, including, VEGF, FGF,and angiopoietin 1 and 2 (Ang1 and Ang2) that bind to their cognatereceptors (VEGFRs, FGFRs and Tie1 and Tie2, respectively) expressed onendothelial cells, as well as platelet-derived growth factor (PDGF) thatbinds to its receptor (PDGFRα) expressed on VEGF-producing stromal cellsor its receptor (PDGFRβ) expressed on pericytes and smooth muscle cellshave been identified. Recent studies indicate that several members ofthe ephrin family and their receptor Eph family are also regulators ofangiogenesis. VEGFRs, FGFRs, Tie1, Tie2, PDGFRs, and Eph receptors allbelong to the receptor protein tyrosine kinase (RTK) superfamily. Giventhe important roles of these RTKs in angiogenesis, their modulationwould be pharmacologically desirable for the treatment of cancer andother disease.

Provided is at least one chemical entity chosen from compounds ofFormula 1

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs, wherein

U, V, and W are chosen from CH and N, provided that no more than two ofU, V, and W are N;

R represents 0 to 2 substituents independently chosen from hydroxy,nitro, cyano, optionally substituted amino, aminocarbonyl, halo,carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl;

R₇ and R₈, taken together with the carbons to which they are bound, forma fused 5- to 7-membered ring chosen from fused 5- to 7-memberedcycloalkyl rings, fused 5- to 7-membered heteroaryl rings and fused 5-to 7-membered heterocyclic rings, wherein the fused 5- to 7-memberedring is substituted with a group —(Z₁)_(m)R₁ wherein

-   -   R₁ is chosen from optionally substituted aryl and optionally        substituted heteroaryl;    -   Z₁ is —CR₅R₆— wherein each R₅ and R₆ is independently chosen        from hydrogen, optionally substituted C₁-C₆ alkyl, and halo; and    -   m is chosen from 0, 1, and 2;

R₂ is optionally substituted aryl; and

R₃ and R₄ are each independently chosen from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted aryl, and optionallysubstituted heteroaryl,

provided that when R₇ and R₈, taken together with the carbons to whichthey are bound, form a fused 5- to 7-membered ring other than a fused4,5-dihydro-1H-imidazole ring, then at least one of U, V, and W isnitrogen.

Also provided is a pharmaceutical composition, comprising at least onechemical entity described herein, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Also provided is a packaged pharmaceutical composition, comprising thepharmaceutical composition described herein in a container; andinstructions for using the composition to treat a patient suffering froma disease or disorder responsive to kinase activity modulation of one ormore tyrosine kinase.

Also provided is a method of treating a patient having a disease ordisorder responsive to kinase activity modulation comprisingadministering to the patient a therapeutically effective amount of atleast one chemical entity described herein or a pharmaceuticalcomposition described herein.

Also provided is a method of modulating EphB₄ kinase activity, themethod comprising contacting cells expressing EphB₄ with at least onechemical entity described herein in an amount sufficient to detectablyinhibit EphB₄ kinase activity in vitro.

Also provided is a method of modulating VEGFR2 kinase activity, themethod comprising contacting cells expressing VEGFR2 with at least onechemical entity described herein in an amount sufficient to detectablyinhibit VEGFR2 kinase activity in vitro.

Also described is a method of modulating c-Kit kinase activity, themethod comprising contacting cells expressing c-Kit with at least onechemical entity described herein in an amount sufficient to detectablyinhibit c-Kit kinase activity in vitro.

Also provided is a method of modulating PDGFRβ kinase activity, themethod comprising contacting cells expressing PDGFRβ with at least onechemical entity described herein in an amount sufficient to detectablyinhibit PDGFRβ kinase activity in vitro.

Also provided is a method of modulating an activity of at least onekinase chosen from VEGFR2, EphB₄, PDGFRβ, and c-Kit, the methodcomprising contacting cells expressing at least one kinase chosen fromVEGFR2, EphB₄, PDGFRβ, and c-Kit with at least one chemical entitydescribed herein in an amount sufficient to detectably inhibit theactivity of at least one kinase chosen from VEGFR2, EphB₄, PDGFRβ, andc-Kit in vitro.

Also described is the use of at least one chemical entity for themanufacture of a medicament for the treatment of a patient having adisease responsive to inhibition of at least one kinase chosen fromVEGFR2, EphB₄, PDGFRβ, and c-Kit, wherein the at least one chemicalentity is a chemical entity described herein.

Also described is a method for the manufacture of a medicament for thetreatment of a patient having a disease responsive to inhibition of atleast one kinase chosen from VEGFR2, EphB₄, PDGFRβ, and c-Kit,comprising including in said medicament at least one chemical entitydescribed herein.

Also described is a method for determining the presence of an angiogenickinase in a sample, comprising contacting the sample with at least onechemical entity described herein under conditions that permit detectionof an activity of the angiogenic kinase, detecting a level of theactivity of the angiogenic kinase in the sample, and therefromdetermining the presence or absence of the angiogenic kinase in thesample.

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise. The following abbreviations and terms have the indicatedmeanings throughout:

Formula 1 includes all subformulae thereof. For example Formula 1includes compounds of Formulae 2 to 9.

As used herein, when any variable occurs more than one time in achemical formula, its definition on each occurrence is independent ofits definition at every other occurrence. In accordance with the usualmeaning of “a” and “the” in patents, reference, for example, to “a”kinase or “the” kinase is inclusive of one or more kinases.

A dash (“-”) that is not between two letters or symbols is used toindicate a point of attachment for a substituent. For example, —CONH₂ isattached through the carbon atom.

By “optional” or “optionally” is meant that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optionally substituted alkyl”encompasses both “alkyl” and “substituted alkyl” as defined below. Itwill be understood by those skilled in the art, with respect to anygroup containing one or more substituents, that such groups are notintended to introduce any substitution or substitution patterns that aresterically impractical, synthetically non-feasible and/or inherentlyunstable.

“Alkyl” encompasses straight chain and branched chain having theindicated number of carbon atoms, usually from 1 to 20 carbon atoms, forexample 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. For exampleC₁-C₆ alkyl encompasses both straight and branched chain alkyl of from 1to 6 carbon atoms. Examples of alkyl groups include methyl, ethyl,propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl,isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and thelike. Alkylene is another subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment. Alkylene groupswill usually have from 2 to 20 carbon atoms, for example, 2 to 8 carbonatoms, such as from 2 to 6 carbon atoms. For example, C₀ alkyleneindicates a covalent bond and C₁ alkylene is a methylene group. When analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, “butyl” is meant to include n-butyl,sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl andisopropyl. “Lower alkyl” refers to alkyl groups having one to fourcarbons.

“Cycloalkyl” indicates a saturated or unsaturated hydrocarbon ringgroup, having the specified number of carbon atoms, usually from 3 to 7ring carbon atoms, provided that the ring is not aromatic. Examples ofcycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, andcyclohexyl as well as bridged and caged saturated ring groups such asnorbornane.

By “alkoxy” is meant an alkyl group of the indicated number of carbonatoms attached through an oxygen bridge such as, for example, methoxy,ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy,2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,3-methylpentoxy, and the like. “Lower alkoxy” refers to alkoxy groupshaving one to four carbons.

“Mono- and di-alkylcarboxamide” encompasses a group of the formula—(C═O)NR_(a)R_(b) where R_(a) and R_(b) are independently chosen fromhydrogen and alkyl groups of the indicated number of carbon atoms,provided that R_(a) and R_(b) are not both hydrogen.

By “alkylthio” is meant an alkyl group of the indicated number of carbonatoms attached through a sulfur bridge.

“Acyl” refers to the groups (alkyl)-C(O)—; (cycloalkyl)-C(O)—;(aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, whereinthe group is attached to the parent structure through the carbonylfunctionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl are as described herein. Acyl groups have the indicatednumber of carbon atoms, with the carbon of the keto group being includedin the numbered carbon atoms. For example a C₂ acyl group is an acetylgroup having the formula CH₃(C═O)—.

By “alkoxycarbonyl” is meant an ester group of the formula(alkoxy)(C═O)— attached through the carbonyl carbon wherein the alkoxygroup has the indicated number of carbon atoms. Thus a C₁-C₆alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atomsattached through its oxygen to a carbonyl linker.

By “amino” is meant the group —NH₂.

“Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkylamino groups, wherein the alkyl groups are as defined above and have theindicated number of carbon atoms. The point of attachment of thealkylamino group is on the nitrogen. Examples of mono- and di-alkylaminogroups include ethylamino, dimethylamino, and methyl-propylamino.

“Mono- and di-(alkyl)aminoalkyl” encompasses mono- and di-(alkyl)aminoas defined above linked to an alkyl group.

By “amino(alkyl)” is meant an amino group linked to an alkyl grouphaving the indicated number of carbons. Similarly “hydroxyalkyl” is ahydroxy group linked to an alkyl group.

The term “aminocarbonyl” refers to the group —CONR^(b)R^(c), where

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c) taken together with the nitrogen to which they arebound, form an optionally substituted 5- to 7-memberednitrogen-containing heterocycloalkyl which optionally includes 1 or 2additional heteroatoms selected from O, N, and S in the heterocycloalkylring;

where each substituted group is independently substituted with one ormore substituents independently selected from C₁-C₄ alkyl, aryl,heteroaryl, aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄haloalkyl-, —OC₁-C₄ alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄haloalkyl, halo, —OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄alkyl), —NH(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄alkylphenyl), cyano, nitro, oxo (as a substitutent for heteroaryl),—CO₂H, —C(O)OC₁-C₄ alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄alkyl), —CONH₂, —NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄alkyl)C(O)(C₁-C₄ alkyl), —N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl,—C(O)C₁-C₄ phenyl, —C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄alkyl), —SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄alkyl), —SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and—NHSO₂(C₁-C₄ haloalkyl).

“Aryl” encompasses:

-   -   5- and 6-membered carbocyclic aromatic rings, for example,        benzene;    -   bicyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, naphthalene, indane, and tetralin;        and    -   tricyclic ring systems wherein at least one ring is carbocyclic        and aromatic, for example, fluorene.        For example, aryl includes 5- and 6-membered carbocyclic        aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring        containing 1 or more heteroatoms chosen from N, O, and S. For        such fused, bicyclic ring systems wherein only one of the rings        is a carbocyclic aromatic ring, the point of attachment may be        at the carbocyclic aromatic ring or the heterocycloalkyl ring.        Bivalent radicals formed from substituted benzene derivatives        and having the free valences at ring atoms are named as        substituted phenylene radicals. Bivalent radicals derived from        univalent polycyclic hydrocarbon radicals whose names end in        “-yl” by removal of one hydrogen atom from the carbon atom with        the free valence are named by adding “-idene” to the name of the        corresponding univalent radical, e.g., a naphthyl group with two        points of attachment is termed naphthylidene. Aryl, however,        does not encompass or overlap in any way with heteroaryl,        separately defined below. Hence, if one or more carbocyclic        aromatic rings is fused with a heterocycloalkyl aromatic ring,        the resulting ring system is heteroaryl, not aryl, as defined        herein.

The term “aryloxy” refers to the group —O-aryl.

The term “halo” includes fluoro, chloro, bromo, and iodo, and the term“halogen” includes fluorine, chlorine, bromine, and iodine.

“Haloalkyl” indicates alkyl as defined above having the specified numberof carbon atoms, substituted with 1 or more halogen atoms, generally upto the maximum allowable number of halogen atoms. Examples of haloalkylinclude, but are not limited to, trifluoromethyl, difluoromethyl,2-fluoroethyl, and penta-fluoroethyl.

“Heteroaryl” encompasses:

-   -   5- to 7-membered aromatic, monocyclic rings containing one or        more, for example, from 1 to 4, or in certain embodiments, from        1 to 3, heteroatoms chosen from N, O, and S, with the remaining        ring atoms being carbon; and    -   bicyclic heterocycloalkyl rings containing one or more, for        example, from 1 to 4, or in certain embodiments, from 1 to 3,        heteroatoms chosen from N, O, and S, with the remaining ring        atoms being carbon and wherein at least one heteroatom is        present in an aromatic ring.

For example, heteroaryl includes a 5- to 7-membered aromatic, monocyclicring containing one or more, for example, from 1 to 4, or in certainembodiments, from 1 to 3, heteroatoms chosen from N, O, and S, with theremaining ring atoms being carbon, fused to a 5- to 7-memberedcycloalkyl ring. For such fused, bicyclic heteroaryl ring systemswherein only one of the rings contains one or more heteroatoms, thepoint of attachment may be at the heteroaromatic ring or the cycloalkylring. When the total number of S and O atoms in the heteroaryl groupexceeds 1, those S and O heteroatoms are not adjacent to one another. Incertain embodiments, the total number of S and O atoms in the heteroarylgroup is not more than 2. In certain embodiments, the total number of Sand O atoms in the aromatic heterocycle is not more than 1. Examples ofheteroaryl groups include, but are not limited to, systems (as numberedfrom the linkage position assigned priority 1), such as 2-pyridyl,3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl,3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl,oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl,benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl,pyridizinyl, triazolyl, quinolinyl, pyrazolyl, and5,6,7,8-tetrahydroisoquinoline. Bivalent radicals derived from univalentheteroaryl radicals whose names end in “-yl” by removal of one hydrogenatom from the atom with the free valence are named by adding “-idene” tothe name of the corresponding univalent radical, e.g., a pyridyl groupwith two points of attachment is a pyridylidene. Heteroaryl does notencompass or overlap with aryl as defined above. Substituted heteroarylalso includes ring systems substituted with one or more oxide (—O⁻)substituents, such as pyridinyl N-oxides.

In the term “heteroarylalkyl,” heteroaryl and alkyl are as definedherein, and the point of attachment is on the alkyl group. This termencompasses, but is not limited to, pyridylmethyl, thiophenylmethyl, and(pyrrolyl)1-ethyl.

By “heterocycloalkyl” is meant a saturated or unsaturated aliphatic ringcontaining at least 2 carbon atoms in addition to 1-3 heteroatomsindependently selected from oxygen, sulfur, and nitrogen, as well ascombinations comprising at least one of the foregoing heteroatoms,provided that the ring is not aromatic. Suitable heterocycloalkyl groupsinclude, for example (as numbered from the linkage position assignedpriority 1), 2-pyrrolinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl,2-piperidyl, 3-piperidyl, 4-piperdyl, and 2,5-piperzinyl. Morpholinyland thiomorpholinyl groups are also contemplated, including2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assignedpriority 1). Heterocycloalkyl also includes ring systems substitutedwith one or more oxo moieties, such as piperidinyl N-oxide,morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and1,1-dioxo-1-thiomorpholinyl. Substituted heterocycloalkyl also includesring systems substituted with one or more oxo (═O) or oxide (—O⁻)substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide,1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.

As used herein, “modulation” refers to a change in kinase activity as adirect or indirect response to the presence of compounds of Formula 1,relative to the activity of the kinase in the absence of the compound.The change may be an increase in activity or a decrease in activity, andmay be due to the direct interaction of the compound with the kinase, ordue to the interaction of the compound with one or more other factorsthat in turn affect kinase activity. For example, the presence of thecompound may, for example, increase or decrease kinase activity bydirectly binding to the kinase, by causing (directly or indirectly)another factor to increase or decrease the kinase activity, or by(directly or indirectly) increasing or decreasing the amount of kinasepresent in the cell or organism.

The term “sulfanyl” includes the groups: —S-(optionally substitutedalkyl), —S-(optionally substituted aryl), —S-(optionally substitutedheteroaryl), and —S-(optionally substituted heterocycloalkyl). Hence,sulfanyl includes the group C₁-C₆ alkylsulfanyl.

The term “sulfinyl” includes the groups: —S(O)—H, —S(O)-(optionallysubstituted alkyl), —S(O)-optionally substituted aryl), —S(O)-optionallysubstituted heteroaryl), —S(O)-(optionally substitutedheterocycloalkyl); and —S(O)-(optionally substituted amino).

The term “sulfonyl” includes the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-optionally substituted heteroaryl), —S(O₂)-(optionallysubstituted heterocycloalkyl), —S(O₂)-(optionally substituted alkoxy),—S(O₂)-optionally substituted aryloxy), —S(O₂)-optionally substitutedheteroaryloxy), —S(O₂)-(optionally substituted heterocyclyloxy); and—S(O₂)-(optionally substituted amino).

The term “substituted”, as used herein, means that any one or morehydrogens on the designated atom or group is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalence is not exceeded. When a substituent is oxo (i.e., ═O) then 2hydrogens on the atom are replaced. Combinations of substituents and/orvariables are permissible only if such combinations result in stablecompounds or useful synthetic intermediates. A stable compound or stablestructure is meant to imply a compound that is sufficiently robust tosurvive isolation from a reaction mixture, and subsequent formulation asan agent having at least practical utility. Unless otherwise specified,substituents are named into the core structure. For example, it is to beunderstood that when (cycloalkyl)alkyl is listed as a possiblesubstituent, the point of attachment of this substituent to the corestructure is in the alkyl portion.

The terms “substituted” alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl, unless otherwise expressly defined, refer respectively toalkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one ormore (such as up to 5, further such as up to 3) hydrogen atoms arereplaced by a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NRCCOR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —SOR^(a), —SO₂R^(a), —SO₂NR^(b)R^(c), and—NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted acyl” refers to the groups (substitutedalkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—;(substituted heteroaryl)-C(O)—; and (substitutedheterocycloalkyl)-C(O)—, wherein the group is attached to the parentstructure through the carbonyl functionality and wherein substitutedalkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, referrespectively to alkyl, cycloalkyl, aryl, heteroaryl, andheterocycloalkyl wherein one or more (such as up to 5, further such asup to 3) hydrogen atoms are replaced by a substituent independentlychosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted alkoxy” refers to alkoxy wherein the alkylconstituent is substituted (i.e., —O-(substituted alkyl)) wherein“substituted alkyl” refers to alkyl wherein one or more (such as up to5, further such as up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl). In some embodiments, a substituted alkoxy group is“polyalkoxy” or —O-(optionally substituted alkylene)-(optionallysubstituted alkoxy), and includes groups such as —OCH₂CH₂OCH₃, andresidues of glycol ethers such as polyethyleneglycol, and—O(CH₂CH₂O)_(x)CH₃, where x is an integer of 2-20, such as 2-10, and forexample, 2-5. Another substituted alkoxy group is hydroxyalkoxy or—OCH₂(CH₂)_(y)OH, where y is an integer of 1-10, such as 1-4.

The term “substituted alkoxycarbonyl” refers to the group (substitutedalkyl)O—C(O)— wherein the group is attached to the parent structurethrough the carbonyl functionality and wherein substituted refers toalkyl wherein one or more (such as up to 5, further such as up to 3)hydrogen atoms are replaced by a substituent independently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl).

The term “substituted amino” refers to the group —NHR^(d) or—NR^(d)R^(d) where each R^(d) is independently chosen from: optionallysubstituted alkyl, optionally substituted cycloalkyl, optionallysubstituted acyl, optionally substituted aminocarbonyl, optionallysubstituted aryl, optionally substituted heteroaryl, optionallysubstituted heterocycloalkyl, alkoxycarbonyl, sulfinyl and sulfonyl,wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, andheteroaryl refer respectively to alkyl, cycloalkyl, aryl,heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5,further such as up to 3) hydrogen atoms are replaced by a substituentindependently chosen from:

—R^(a), —OR^(b), —O(C₁-C₂ alkyl)O— (e.g., methylenedioxy-), —SR^(b),guanidine, guanidine wherein one or more of the guanidine hydrogens arereplaced with a lower-alkyl group, —NR^(b)R^(c), halo, cyano, nitro,—COR^(b), —CO₂R^(b), —CONR^(b)R^(c), —OCOR^(b), —OCO₂R^(a),—OCONR^(b)R^(c), —NR^(c)COR^(b), —NR^(c)CO₂R^(a), —NR^(c)CONR^(b)R^(c),—CO₂R^(b), —CONR^(b)R^(c), —NR^(c)COR^(b), —SOR^(a), —SO₂R^(a),—SO₂NR^(b)R^(c), and —NR^(c)SO₂R^(a),

where R^(a) is chosen from optionally substituted C₁-C₆ alkyl,optionally substituted aryl, and optionally substituted heteroaryl;

R^(b) is chosen from H, optionally substituted C₁-C₆ alkyl, optionallysubstituted aryl, and optionally substituted heteroaryl; and

R^(c) is chosen from hydrogen and optionally substituted C₁-C₄ alkyl; or

R^(b) and R^(c), and the nitrogen to which they are attached, form anoptionally substituted heterocycloalkyl group; and

where each optionally substituted group is unsubstituted orindependently substituted with one or more, such as one, two, or three,substituents independently selected from C₁-C₄ alkyl, aryl, heteroaryl,aryl-C₁-C₄ alkyl-, heteroaryl-C₁-C₄ alkyl-, C₁-C₄ haloalkyl-, —OC₁-C₄alkyl, —OC₁-C₄ alkylphenyl, —C₁-C₄ alkyl-OH, —OC₁-C₄ haloalkyl, halo,—OH, —NH₂, —C₁-C₄ alkyl-NH₂, —N(C₁-C₄ alkyl)(C₁-C₄ alkyl), —NH(C₁-C₄alkyl), —N(C₁-C₄ alkyl)(C₁-C₄ alkylphenyl), —NH(C₁-C₄ alkylphenyl),cyano, nitro, oxo (as a substitutent for heteroaryl), —CO₂H, —C(O)OC₁-C₄alkyl, —CON(C₁-C₄ alkyl)(C₁-C₄ alkyl), —CONH(C₁-C₄ alkyl), —CONH₂,—NHC(O)(C₁-C₄ alkyl), —NHC(O)(phenyl), —N(C₁-C₄ alkyl)C(O)(C₁-C₄ alkyl),—N(C₁-C₄ alkyl)C(O)(phenyl), —C(O)C₁-C₄ alkyl, —C(O)C₁-C₄ phenyl,—C(O)C₁-C₄ haloalkyl, —OC(O)C₁-C₄ alkyl, —SO₂(C₁-C₄ alkyl),—SO₂(phenyl), —SO₂(C₁-C₄ haloalkyl), —SO₂NH₂, —SO₂NH(C₁-C₄ alkyl),—SO₂NH(phenyl), —NHSO₂(C₁-C₄ alkyl), —NHSO₂(phenyl), and —NHSO₂(C₁-C₄haloalkyl); and

wherein optionally substituted acyl, optionally substitutedaminocarbonyl, alkoxycarbonyl, sulfinyl and sulfonyl are as definedherein.

The term “substituted amino” also refers to N-oxides of the groups—NHR^(d) and —NR^(d)R^(d), each as described above. N-oxides can beprepared by treatment of the corresponding amino group with, forexample, hydrogen peroxide or m-chloroperoxybenzoic acid. The personskilled in the art is familiar with reaction conditions for carrying outthe N-oxidation.

Compounds of Formula 1 include, but are not limited to, optical isomersof compounds of Formula 1, racemates, and other mixtures thereof. Inthose situations, the single enantiomers or diastereomers, i.e.,optically active forms, can be obtained by asymmetric synthesis or byresolution of the racemates. Resolution of the racemates can beaccomplished, for example, by conventional methods such ascrystallization in the presence of a resolving agent, or chromatography,using, for example a chiral high-pressure liquid chromatography (HPLC)column. In addition, compounds of Formula I include Z- and E-forms (orcis- and trans-forms) of compounds with carbon-carbon double bonds.Where compounds of Formula 1 exists in various tautomeric forms,chemical entities of the present invention include all tautomeric formsof the compound. Compounds of Formula 1 also include crystal formsincluding polymorphs and clathrates.

Chemical entities of the present invention include, but are not limitedto compounds of Formula 1 and all pharmaceutically acceptable formsthereof. Pharmaceutically acceptable forms of the compounds recitedherein include pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, and prodrugs thereof. In certain embodiments,the compounds described herein are in the form of pharmaceuticallyacceptable salts. Hence, the terms “chemical entity” and “chemicalentities” also encompass pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, and prodrugs.

“Pharmaceutically acceptable salts” include, but are not limited tosalts with inorganic acids, such as hydrochlorate, phosphate,diphosphate, hydrobromate, sulfate, sulfinate, nitrate, and like salts;as well as salts with an organic acid, such as malate, maleate,fumarate, tartrate, succinate, citrate, acetate, lactate,methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate,salicylate, stearate, and alkanoate such as acetate, HOOC—(CH₂)_(n)—COOHwhere n is 0-4, and like salts. Similarly, pharmaceutically acceptablecations include, but are not limited to sodium, potassium, calcium,aluminum, lithium, and ammonium.

In addition, if the compound of Formula 1 is obtained as an acidaddition salt, the free base can be obtained by basifying a solution ofthe acid salt. Conversely, if the product is a free base, an additionsalt, particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds. Thoseskilled in the art will recognize various synthetic methodologies thatmay be used to prepare non-toxic pharmaceutically acceptable additionsalts.

As noted above, prodrugs also fall within the scope of chemicalentities, for example ester or amide derivatives of the compounds ofFormula 1. The term “prodrugs” includes any compounds that becomecompounds of Formula 1 when administered to a patient, e.g., uponmetabolic processing of the prodrug. Examples of prodrugs include, butare not limited to, acetate, formate, and benzoate and like derivativesof functional groups (such as alcohol or amine groups) in the compoundsof Formula 1.

The term “solvate” refers to the chemical entity formed by theinteraction of a solvent and a compound. Suitable solvates arepharmaceutically acceptable solvates, such as hydrates, includingmonohydrates and hemi-hydrates.

The term “chelate” refers to the chemical entity formed by thecoordination of a compound to a metal ion at two (or more) points.

The term “non-covalent complex” refers to the chemical entity formed bythe interaction of a compound and another molecule wherein a covalentbond is not formed between the compound and the molecule. For example,complexation can occur through van der Waals interactions, hydrogenbonding, and electrostatic interactions (also called ionic bonding).

The term “active agent” is used to indicate a chemical entity which hasbiological activity. In certain embodiments, an “active agent” is acompound having pharmaceutical utility. For example an active agent maybe an anti-cancer therapeutic.

The term “therapeutically effective amount” of a chemical entity of thisinvention means an amount effective, when administered to a human ornon-human patient, to treat a disease, e.g., a therapeutically effectiveamount may be an amount sufficient to treat a disease or disorderresponsive to kinase inhibition. The therapeutically effective amountmay be ascertained experimentally, for example by assaying bloodconcentration of the chemical entity, or theoretically, by calculatingbioavailability.

By “significant” is meant any detectable change that is statisticallysignificant in a standard parametric test of statistical significancesuch as Student's T-test, where p<0.05.

“Patient” refers to an animal, such as a mammal, for example a human,that has been or will be the object of treatment, observation orexperiment. The methods of the invention can be useful in both humantherapy and veterinary applications. In some embodiments, the patient isa mammal, and in some embodiments the patient is human. In someembodiments, the patient is chosen from cats and dogs.

By “angiogenic kinase” is meant a kinase involved in angiogenesis andincludes but is not limited to a kinase chosen from EphB₄ VEGFR2 andPDGFRβ.

By “oncogenic kinase” is meant a kinase having a direct role in a cellsignaling pathway that leads to cellular transformation. Whenoverexpressed or aberrantly expressed, such kinases may have oncogenicactivity. Oncogenic kinases include but are not limited to c-Kit.

“Treatment” or “treating” means any treatment of a disease in a patient,including:

-   -   a) preventing the disease, that is, causing the clinical        symptoms of the disease not to develop;    -   b) inhibiting the disease;    -   c) slowing or arresting the development of clinical symptoms;        and/or    -   d) relieving the disease, that is, causing the regression of        clinical symptoms.

“Diseases or disorders responsive to kinase modulation” refer topathologic conditions that depend, at least in part, on the activity ofone or more protein kinases, for example, angiogenic kinases and/oroncogenic kinases. Kinases either directly or indirectly participate inthe signal transduction pathways of a variety of cellular activitiesincluding cell proliferation, differentiation, and invasion. Diseasesresponsive to kinase modulation include but are not limited to tumorgrowth, angiogenesis supporting solid tumor growth, and diseasescharacterized by excessive local vascularization such as diabeticretinopathy, macular degeneration, and inflammation.

“Change in angiogenesis” refers to a change in the vascular network orquality of vasculature. Change in angiogenesis may be measured by manyparameters and, for instance, may be assessed by delayed appearance ofneovascular structures, slowed development of neovascular structures,decreased occurrence of neovascular structures, changes in vascularpermeability, changes in blood flow, slowed or decreased severity ofangiogenesis-dependent disease effects, arrested angiogenic growth, orregression of previous angiogenic growth.

Provided herein is at least one chemical entity chosen from compounds ofFormula 1

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein

U, V, and W are chosen from CH and N, provided that no more than two ofU, V, and W are N;

R represents 0 to 2 substituents independently chosen from hydroxy,nitro, cyano, optionally substituted amino, aminocarbonyl, halo,carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl;

R₇ and R₈, taken together with the carbons to which they are bound, forma fused 5- to 7-membered ring chosen from fused 5- to 7-memberedcycloalkyl rings, fused 5- to 7-membered heteroaryl rings and fused 5-to 7-membered heterocyclic rings, wherein the fused 5- to 7-memberedring is substituted with a group —(Z₁)_(m)R₁ wherein

-   -   R₁ is chosen from optionally substituted aryl and optionally        substituted heteroaryl;    -   Z₁ is —CR₅R₆— wherein each R₅ and R₆ is independently chosen        from hydrogen, optionally substituted C₁-C₆ alkyl, and halo; and    -   m is chosen from 0, 1, and 2;

R₂ is optionally substituted aryl; and

R₃ and R₄ are each independently chosen from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted aryl, and optionallysubstituted heteroaryl,

provided that when R₇ and R₈, taken together with the carbons to whichthey are bound, form a fused 5- to 7-membered ring other than a fused4,5-dihydro-1H-imidazole ring, then at least one of U, V, and W isnitrogen.

In certain embodiments, R₇ and R₈, taken together with the carbons towhich they are bound, form a substituted fused ring chosen fromsubstituted pyrazolyl, substituted imidazolyl, substituted isoxazolyl,substituted oxazolyl, substituted thiazolyl, substituted thiadiazolyl,substituted triazolyl, substituted 4,5-dihydro-1H-imidazolyl, andsubstituted pyrrolyl.

In certain embodiments, R₇ and R₈, taken together with the carbons towhich they are bound, form a substituted fused heteroaryl ring chosenfrom substituted 4,5-dihydro-1H-imidazolyl, substituted 1H-pyrrolyl andsubstituted 1H-pyrazolyl.

In certain embodiments, Z₁ is —CR₅R₆— and at least one of R₅ and R₆ ishydrogen. In certain embodiments, both of R₅ and R₆ are hydrogen.

In certain embodiments, m is 0. In certain embodiments, m is 1. Incertain embodiments, m is 2.

In certain embodiments, m is 1 and at least one of R₅ and R₆ ishydrogen. In certain embodiments, m is 1 and both of R₅ and R₆ arehydrogen.

In certain embodiments, R₁ is optionally substituted heteroaryl.

In certain embodiments, R₁ is chosen from pyridinyl, substitutedpyridinyl,

wherein Q is chosen from CH and N, T is chosen from CH, N, and O, andthe wavy line represents the attachment point of R₁ to Z₁.

In certain embodiments, R₁ is chosen from pyridinyl and substitutedpyridinyl wherein substituted pyridinyl is chosen from mono-, di-, andtri-substituted pyridinyls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, optionally substituted amino,aminocarbonyl, halo, carboxy, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl,optionally substituted aryl, optionally substituted heteroaryl, andoptionally substituted heterocycloalkyl.

In certain embodiments, R₁ is chosen from pyridinyl and substitutedpyridinyl wherein substituted pyridinyl is chosen from mono-, di-, andtri-substituted pyridinyls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, optionally substituted amino, halo,carboxy, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ acyl, C₁-C₆ alkoxycarbonyl,optionally substituted heteroaryl, and optionally substitutedheterocycloalkyl.

In certain embodiments, R₁ is chosen from pyridinyl and substitutedpyridinyl wherein substituted pyridinyl is chosen from mono-, di-, andtri-substituted pyridinyls and wherein substituents are independentlychosen from hydroxy, cyano, halo, optionally substituted C₁-C₂ alkyl,and optionally substituted C₁-C₂ alkoxy.

In certain embodiments, R₁ is chosen from pyridin-4-yl and substitutedpyridin-4-yl wherein substituted pyridin-4-yl is chosen from mono-, di-,and tri-substituted pyridin-4-yls and wherein substituents areindependently chosen from hydroxy, nitro, cyano, optionally substitutedamino, aminocarbonyl, halo, carboxy, optionally substituted acyl,optionally substituted alkoxycarbonyl, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ alkoxy, sulfanyl, sulfinyl,sulfonyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocycloalkyl.

In certain embodiments, R₁ is chosen from pyridin-4-yl and substitutedpyridin-4-yl wherein substituted pyridin-4-yl is chosen from mono-, di-,and tri-substituted pyridin-4-yls and wherein substituents areindependently chosen from hydroxy, nitro, cyano, optionally substitutedamino, halo, carboxy, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, C₁-C₆ alkylsulfanyl, C₁-C₆ acyl, C₁-C₆alkoxycarbonyl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl.

In certain embodiments, R₁ is chosen from pyridin-4-yl and substitutedpyridin-4-yl wherein substituted pyridin-4-yl is chosen from mono-, di-,and tri-substituted pyridin-4-yls and wherein substituents areindependently chosen from hydroxy, cyano, halo, optionally substitutedC₁-C₂ alkyl, and optionally substituted C₁-C₂ alkoxy. In certainembodiments, R₁ is pyridin-4-yl.

In some embodiments, R represents 1 or 2 substituents independentlychosen from halo, C₁-C₂ alkyl, and C₁-C₂ alkoxy. In some embodiments, Rrepresents 1 or 2 substituents independently chosen from halo, methyl,and methoxy. In some embodiments R represents a substituent chosen fromhalo, methyl, and methoxy. In some embodiments, R is absent.

In certain embodiments, R₂ is chosen from phenyl, substituted phenyl,

wherein

A is chosen from CH₂ and O,

D is chosen from CH and N,

the wavy line represents the attachment point of R₂ to the urea group ofFormula 1, and

R₉ is chosen from hydroxy, nitro, cyano, optionally substituted amino,aminocarbonyl, halo, carboxy, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted aryloxy,sulfanyl, sulfinyl, sulfonyl, optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl.

In certain embodiments, R₂ is chosen from phenyl and substituted phenylwherein substituted phenyl is chosen from mono-, di-, andtri-substituted phenyls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, optionally substituted amino,aminocarbonyl, halo, carboxy, optionally substituted acyl, optionallysubstituted alkoxycarbonyl, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted aryloxy,sulfanyl, sulfinyl, sulfonyl, optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl.

In certain embodiments, R₂ is chosen from phenyl and substituted phenylwherein substituted phenyl is chosen from mono-, di-, andtri-substituted phenyls and wherein substituents are independentlychosen from hydroxy, nitro, cyano, optionally substituted amino, halo,carboxy, optionally substituted C₁-C₆ alkyl, optionally substitutedC₁-C₆ alkoxy, optionally substituted phenoxy, C₁-C₆ alkylsulfanyl, C₁-C₆acyl, C₁-C₆ alkoxycarbonyl, optionally substituted heteroaryl, andoptionally substituted heterocycloalkyl.

In certain embodiments, R₂ is chosen from phenyl and substituted phenylwherein substituted phenyl is chosen from mono-, di-, andtri-substituted phenyls and wherein substituents are independentlychosen from hydroxy, cyano, halo, optionally substituted C₁-C₂ alkyl,phenoxy, and optionally substituted C₁-C₂ alkoxy.

In certain embodiments, R₂ is chosen from phenyl and substituted phenylwherein substituted phenyl is chosen from mono-, di-, andtri-substituted phenyls and wherein substituents are independentlychosen from halo, methyl, methoxy, ethoxy, and trifluoromethyl.

In certain embodiments, R₃ and R₄ are each independently chosen fromhydrogen and methyl. In certain embodiments, R₃ and R₄ are hydrogen.

Also provided is at least one chemical entity chosen from compounds ofFormula 2

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein U, V, W, R, R₁, Z₁, m, R₂, R₃and R₄ are as described for compounds of Formula 1, and further whereinX is chosen from CH and N.

In certain embodiments, X is N. In certain embodiments, X is CH.

Also provided is at least one chemical entity chosen from compounds ofFormula 3

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein

U, V, W, R, R₁, Z₁, m, R₂, R₃, and R₄ are as described for compounds ofFormula 1.

Also provided is at least one chemical entity chosen from compounds ofFormula 4

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein X, U, V, W, R, R₂, R₃ and R₄are as described for Formula 2, and further wherein

R₂₀ represents 0 to 3 substituents independently chosen from hydroxy,nitro, cyano, optionally substituted amino, aminocarbonyl, halo,carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl.

In certain embodiments, R₂₀ is absent.

Also provided is at least one chemical entity chosen from compounds ofFormula 5

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein U, V, W, R, R₂, R₃ and R₄ areas described for Formula 3, and further wherein.

R₂₀ represents 0 to 3 substituents independently chosen from hydroxy,nitro, cyano, optionally substituted amino, aminocarbonyl, halo,carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl.

Also provided is at least one chemical entity chosen from compounds ofFormula 6

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein X, U, V, W, R, R₂, R₃, R₄, andR₂₀ are as described for Formula 4.

Also provided is at least one chemical entity chosen from compounds ofFormula 7

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein U, V, W, R, R₂, R₃, R₄, and R₂₀are as described for Formula 5.

Also provided is at least one chemical entity chosen from compounds ofFormula 8

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein X, U, V, W, R, R₃, R₄, and R₂₀are as described for Formula 6 and further wherein

R₂₁ is chosen from hydrogen, halo and optionally substituted loweralkyl;

R₂₂ is chosen from hydrogen, halo, lower alkoxy, and lower alkyl; and

R₂₃ is chosen from hydrogen, lower alkyl, optionally substitutedphenoxy, lower alkoxy, and halo

Also provided is at least one chemical entity chosen from compounds ofFormula 9

and pharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs thereof, wherein U, V, W, Y, R, R₃, R₄, and R₂₀are as described for Formula 5 and further wherein

R₂₁ is chosen from hydrogen, halo and optionally substituted loweralkyl;

R₂₂ is chosen from hydrogen, halo, lower alkoxy, and lower alkyl; and

R₂₃ is chosen from hydrogen, lower alkyl, optionally substitutedphenoxy, lower alkoxy, and halo

In some embodiments, R₂₁ is chosen from hydrogen, halo, methyl, andtrifluoromethyl.

In certain embodiments, R₂₂ is chosen from hydrogen, halo, methoxy, andmethyl. In certain embodiments, R₂₃ is chosen from hydrogen, methyl,methoxy, ethoxy, and halo. In certain embodiments, at least one of R₂₁,R₂₂, and R₂₃ is not hydrogen

In certain embodiments, at least one chemical entity is chosen from

-   1-(5-bromo-2-methoxyphenyl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)urea;-   1-(5-chloro-2-methoxyphenyl)-3-(1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)urea;-   1-(5-Bromo-2-methoxy-phenyl)-3-(1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(5-Bromo-2-methoxy-phenyl)-3-(1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(5-Bromo-2-methoxy-phenyl)-3-(5-methyl-1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(5-Bromo-2-methoxy-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;-   1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;    and-   1-(5-Methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-3-(4-methyl-3-trifluoromethylphenyl)-urea;    and    pharmaceutically acceptable salts, solvates, chelates, non-covalent    complexes, and prodrugs thereof.

Methods for obtaining the novel compounds described herein will beapparent to those of ordinary skill in the art, suitable proceduresbeing described, for example, in the reaction scheme and example below,and in the references cited herein.

Referring to Reaction Scheme 1, Step 1, an excess (such as about 1.5equivalents) of a compound of Formula 101 in an inert solvent such asDMF is cooled to about −15° C. An excess (such as about 2 equivalents)of a base, such as sodium hydride (for example, a 60% dispersion ofsodium hydride in mineral oil) is then added and the reaction is stirredat about −15° C. for about 25 min. A compound of Formula R₁-(Z₁)_(m)-Qwherein Q is a leaving group, for example, halo, is added and thereaction mixture is stirred at about −15° C. for a further 5 min. Aftersuch time the cooling bath is removed and the reaction is stirred forabout 30 min at ambient temperature. Additional compound of FormulaR₁-(Z₁)_(m)-Q and base may be added and the reaction may be stirred atambient temperature for an additional 30 minutes. The product, acompound of Formula 103, is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 2, to a solution of about 0.3equivalent of rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl, about 0.1equivalent of Pd₂dba₃, and an excess (such as about 1.4 equivalents) ofa base, such as sodium tert-butoxide is added a solution of a compoundof Formula 103 in an inert solvent such as toluene followed by an excess(such as about 1.2 equivalents) of benzophenone imine. The reaction isheated at reflux for about 2 h. The product, a compound of Formula 105,is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 3, a solution of a compound ofFormula 105 in an inert solvent such as THF is treated with acid, suchas aqueous hydrochloric acid, for example, 2N hydrochloric acid. Thereaction is stirred at room temperature for about 1 h. The product, acompound of Formula 107, is isolated and optionally purified.

Referring to Reaction Scheme 1, Step 4, to a solution of a compound ofFormula 107 in an inert solvent such as dichloromethane and/ordimethylformamide (for example, 3:1 dichloromethane:dimethylformamide)is added about one equivalent of an isocyanate of the formula R₂—NCO.The product, a compound of Formula 109, is isolated and optionallypurified.

Referring to Reaction Scheme 2, Step 1, a solution of a compound ofFormula 201 in 98% sulfuric acid is cooled to about 0° C. and treatedportionwise with potassium nitrate over about 15 minutes. Once the lastaddition is complete, the reaction is stirred for 1 h at 0° C. Theproduct, a compound of Formula 203, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 2, to a solution of about anequivalent of a compound of Formula R₁-(Z₁)_(m)-Q wherein Q is a leavinggroup such as chloro, in an inert solvent such as DMF is added about anequivalent of a base, such as sodium hydride (for example, a 60%dispersion of sodium hydride in mineral oil). The reaction mixture isstirred at room temperature. To the mixture is then added potassiumcarbonate and a compound of Formula 203. The product, a compound ofFormula 205, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 3, a solution of a compound ofFormula 205 and an excess (such as about 1.1 equivalents) of iron powderin acetic acid is stirred at about 50° C. for about 15 min. The product,a compound of Formula 207, is isolated and optionally purified.

Referring to Reaction Scheme 2, Step 4, to a solution of a compound ofFormula 207 in an inert solvent such as CH₂Cl₂ is added about oneequivalent of an isocyanate of the formula R₂—NCO. The product, acompound of Formula 209, is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 1, a solution of a compound ofFormula 301, an excess (such as about 3 equivalents) of triethylorthoformate, and p-toluenesulfonic acid in an inert solvent such astoluene is heated to reflux under nitrogen. The product, a compound ofFormula 303, is isolated and optionally purified.

Referring to Reaction Scheme 3, Step 2, a solution of a compound ofFormula 303, a base such as potassium carbonate, and a compound ofFormula R₁-(Z₁)_(m)-Q wherein Q is a leaving group such as chloro, in aninert solvent such as DMF is stirred at room temperature. The product, acompound of Formula 305, is isolated and optionally purified.

In some embodiments, the chemical entities described herein areadministered as a pharmaceutical composition or formulation.Accordingly, the invention provides pharmaceutical formulationscomprising at least one chemical entity chosen from compounds of Formula1 and pharmaceutically acceptable salts, solvates, chelates,non-covalent complexes, and prodrugs thereof, together with at least onepharmaceutically acceptable vehicle chosen from carriers, adjuvants, andexcipients.

Pharmaceutically acceptable vehicles must be of sufficiently high purityand sufficiently low toxicity to render them suitable for administrationto the patient being treated. The vehicle can be inert or it can possesspharmaceutical benefits. The amount of vehicle employed in conjunctionwith the chemical entity is sufficient to provide a practical quantityof material for administration per unit dose of the chemical entity.

Exemplary pharmaceutically acceptable carriers or components thereof aresugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; synthetic oils; vegetable oils,such as peanut oil, cottonseed oil, sesame oil, olive oil, and corn oil;polyols such as propylene glycol, glycerine, sorbitol, mannitol, andpolyethylene glycol; alginic acid; phosphate buffer solutions;emulsifiers, such as the TWEENS; wetting agents, such as sodium laurylsulfate; coloring agents; flavoring agents; tableting agents;stabilizers; antioxidants; preservatives; pyrogen-free water; isotonicsaline; and phosphate buffer solutions.

Optional active agents may be included in a pharmaceutical composition,which do not substantially interfere with the activity of the chemicalentity of the present invention.

A therapeutically effective amount of at least one chemical entitychosen from compounds of Formula 1 and pharmaceutically acceptablesalts, solvates, chelates, non-covalent complexes, and prodrugs thereof,is mixed with a suitable pharmaceutical acceptable vehicle. In instancesin which the chemical entity exhibits insufficient solubility, methodsfor solubilizing compounds may be used. Such methods are known to thoseof skill in this art, and include, but are not limited to, usingcosolvents, such as dimethylsulfoxide (DMSO), using surfactants, such asTWEEN, or dissolution in aqueous sodium bicarbonate.

Upon mixing or addition of the chemical entity described herein, theresulting mixture may be a solution, suspension, emulsion or the like.The form of the resulting mixture depends upon a number of factors,including the intended mode of administration and the solubility of thechemical entity in the chosen vehicle. The therapeutically effectiveamount of the chemical entity may be empirically determined.

Chemical entities described herein may be administered orally,topically, parenterally, intravenously, by intramuscular injection, byinhalation or spray, sublingually, transdermally, via buccaladministration, rectally, as an ophthalmic solution, or by other means,in dosage unit formulations.

Dosage formulations suitable for oral use, include, for example,tablets, troches, lozenges, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixirs. Compositions intended for oral use may be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agents, suchas sweetening agents, flavoring agents, coloring agents and preservingagents, in order to provide pharmaceutically elegant and palatablepreparations. In some embodiments, oral formulations contain from 0.1 to99% of at least one chemical entity described herein. In someembodiments, oral formulations contain at least 5% (weight %) of atleast one chemical entity described herein. Some embodiments containfrom 25% to 50% or from 5% to 75% of at least one chemical entitydescribed herein.

Orally administered compositions also include liquid solutions,emulsions, suspensions, powders, granules, elixirs, tinctures, syrups,and the like. The pharmaceutically acceptable carriers suitable forpreparation of such compositions are well known in the art. Oralformulations may contain preservatives, flavoring agents, sweeteningagents, such as sucrose or saccharin, taste-masking agents, and coloringagents.

Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. Syrups and elixirs may beformulated with sweetening agents, for example glycerol, propyleneglycol, sorbitol, or sucrose. Such formulations may also contain ademulcent.

Chemical entities described herein can be incorporated into oral liquidpreparations such as aqueous or oily suspensions, solutions, emulsions,syrups, or elixirs, for example. Moreover, formulations comprising thesechemical entities can be presented as a dry product for constitutionwith water or other suitable vehicle before use. Such liquidpreparations can contain conventional additives, such as suspendingagents (e.g., sorbitol syrup, methyl cellulose, glucose/sugar, syrup,gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminumstearate gel, and hydrogenated edible fats), emulsifying agents (e.g.,lecithin, sorbitan monsoleate, or acacia), non-aqueous vehicles, whichcan include edible oils (e.g., almond oil, fractionated coconut oil,silyl esters, propylene glycol and ethyl alcohol), and preservatives(e.g., methyl or propyl p-hydroxybenzoate and sorbic acid).

For a suspension, typical suspending agents include methylcellulose,sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodiumalginate; typical wetting agents include lecithin and polysorbate 80;and typical preservatives include methyl paraben and sodium benzoate.

Aqueous suspensions contain the active material(s) in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are chosen form suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents; naturally-occurring phosphatides, forexample, lecithin, and condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, and condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, and condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol substitute, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan substitute.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example peanut oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or peanut oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.

Tablets typically comprise conventional pharmaceutically acceptableadjuvants as inert diluents, such as calcium carbonate, sodiumcarbonate, mannitol, lactose and cellulose; binders such as starch,gelatin and sucrose; disintegrants such as starch, alginic acid andcroscarmelose; lubricants such as magnesium stearate, stearic acid andtalc. Glidants such as silicon dioxide can be used to improve flowcharacteristics of the powder mixture. Coloring agents, such as the FD&Cdyes, can be added for appearance. Sweeteners and flavoring agents, suchas aspartame, saccharin, menthol, peppermint, and fruit flavors, can beuseful adjuvants for chewable tablets. Capsules (including time releaseand sustained release formulations) typically comprise one or more soliddiluents disclosed above. The selection of carrier components oftendepends on secondary considerations like taste, cost, and shelfstability.

Such compositions may also be coated by conventional methods, typicallywith pH or time-dependent coatings, such that the chemical entity isreleased in the gastrointestinal tract in the vicinity of the desiredtopical application, or at various times to extend the desired action.Such dosage forms typically include, but are not limited to, one or moreof cellulose acetate phthalate, polyvinylacetate phthalate,hydroxypropyl methylcellulose phthalate, ethyl cellulose, Eudragitcoatings, waxes and shellac.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Pharmaceutical compositions may be in the form of a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents that have been mentioned above. The sterileinjectable preparation may also be sterile injectable solution orsuspension in a non-toxic parentally acceptable vehicle, for example asa solution in 1,3-butanediol. Among the acceptable vehicles that may beemployed are water, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid can be useful in the preparation ofinjectables.

Chemical entities described herein may be administered parenterally in asterile medium. Parenteral administration includes subcutaneousinjections, intravenous, intramuscular, intrathecal injection orinfusion techniques. Chemical entities described herein, depending onthe vehicle and concentration used, can either be suspended or dissolvedin the vehicle. Advantageously, adjuvants such as local anesthetics,preservatives and buffering agents can be dissolved in the vehicle. Inmany compositions for parenteral administration the carrier comprises atleast 90% by weight of the total composition. In some embodiments, thecarrier for parenteral administration is chosen from propylene glycol,ethyl oleate, pyrrolidone, ethanol, and sesame oil.

Chemical entites described herein may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient that is solid at ordinary temperatures butliquid at rectal temperature and will therefore melt in the rectum torelease the drug. Such materials include cocoa butter and polyethyleneglycols.

Chemical entities described herein may be formulated for local ortopical application, such as for topical application to the skin andmucous membranes, such as in the eye, in the form of gels, creams, andlotions and for application to the eye. Topical compositions may be inany form including, for example, solutions, creams, ointments, gels,lotions, milks, cleansers, moisturizers, sprays, skin patches, and thelike.

Such solutions may be formulated as 0.01%-10% isotonic solutions, pHfrom 2 to 12, such as from 5 to 7, with appropriate salts. Chemicalentities described herein may also be formulated for transdermaladministration as a transdermal patch.

Topical compositions comprising at least one chemical entity describedherein can be admixed with a variety of carrier materials well known inthe art, such as, for example, water, alcohols, aloe vera gel,allantoin, glycerine, vitamin A and E oils, mineral oil, propyleneglycol, PPG-2 myristyl propionate, and the like.

Other materials suitable for use in topical carriers include, forexample, emollients, solvents, humectants, thickeners and powders.Examples of each of these types of materials, which can be used singlyor as mixtures of one or more materials, are as follows:

Representative emollients include stearyl alcohol, glycerylmonoricinoleate, glyceryl monostearate, propane-1,2-diol,butane-1,3-diol, mink oil, cetyl alcohol, iso-propyl isostearate,stearic acid, iso-butyl palmitate, isocetyl stearate, oleyl alcohol,isopropyl laurate, hexyl laurate, decyl oleate, octadecan-2-ol, isocetylalcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate,iso-propyl myristate, iso-propyl palmitate, iso-propyl stearate, butylstearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil,coconut oil, arachis oil, castor oil, acetylated lanolin alcohols,petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid,isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, andmyristyl myristate; propellants, such as propane, butane, iso-butane,dimethyl ether, carbon dioxide, and nitrous oxide; solvents, such asethyl alcohol, methylene chloride, iso-propanol, castor oil, ethyleneglycol monoethyl ether, diethylene glycol monobutyl ether, diethyleneglycol monoethyl ether, dimethyl sulphoxide, dimethyl formamide,tetrahydrofuran; humectants, such as glycerin, sorbitol, sodium2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, andgelatin; and powders, such as chalk, talc, fullers earth, kaolin,starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetraalkyl ammonium smectites, trialkyl aryl ammonium smectites, chemicallymodified magnesium aluminium silicate, organically modifiedmontmorillonite clay, hydrated aluminium silicate, fumed silica,carboxyvinyl polymer, sodium carboxymethyl cellulose, and ethyleneglycol monostearate.

Chemical entities described herein may also be topically administered inthe form of liposome delivery systems, such as small unilamellarvesicles, large unilamellar vesicles, and multilamellar vesicles.Liposomes can be formed from a variety of phospholipids, such ascholesterol, stearylamine, and phosphatidylcholines.

Other compositions useful for attaining systemic delivery of thechemical entity include sublingual, buccal and nasal dosage forms. Suchcompositions typically comprise one or more of soluble filler substancessuch as sucrose, sorbitol and mannitol, and binders such as acacia,microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropylmethylcellulose. Glidants, lubricants, sweeteners, colorants,antioxidants and flavoring agents disclosed above may also be included.

Compositions for inhalation typically can be provided in the form of asolution, suspension or emulsion that can be administered as a drypowder or in the form of an aerosol using a conventional propellant(e.g., dichlorodifluoromethane or trichlorofluoromethane).

The compositions of the present invention may also optionally comprisean activity enhancer. The activity enhancer can be chosen from a widevariety of molecules that function in different ways to enhance or beindependent of therapeutic effects of the chemical entities describedherein. Particular classes of activity enhancers include skinpenetration enhancers and absorption enhancers.

Pharmaceutical compositions of the invention may also contain additionalactive agents that can be chosen from a wide variety of molecules, whichcan function in different ways to enhance the therapeutic effects of atleast one chemical entity described herein. These optional other activeagents, when present, are typically employed in the compositions of theinvention at a level ranging from 0.01% to 15%. Some embodiments containfrom 0.1% to 10% by weight of the composition. Other embodiments containfrom 0.5% to 5% by weight of the composition.

The invention can include packaged pharmaceutical formulations. Suchpackaged formulations include a pharmaceutical composition comprising atleast one chemical entity chosen from compounds of Formula 1 andpharmaceutically acceptable salts, solvates, chelates, non-covalentcomplexes, and prodrugs, in a container and instructions for using thecomposition to treat a mammal (typically a human patient). In someembodiments, the instructions are for using the pharmaceuticalcomposition to treat a patient suffering from a disease responsive tokinase inhibition. The invention includes providing prescribinginformation; for example, to a patient or health care provider, or as alabel in a packaged pharmaceutical formulation. Prescribing informationmay include for example efficacy, dosage and administration,contraindication and adverse reaction information pertaining to thepharmaceutical formulation.

In all of the foregoing the chemical entities can be administered alone,as mixtures, or in combination with other active agents.

The compounds of the present invention can be useful for the treatmentof diseases and disorders responsive to kinase modulation. As usedherein, “modulation” refers to a change in kinase activity as a director indirect response to the presence of at least one chemical entitydescribed herein, relative to the activity of the kinase in the absenceof the chemical entity. The change may be an increase in activity or adecrease in activity, and may be due to the direct interaction of thechemical entity with the kinase, or due to the interaction of thechemical entity with one or more other factors that in turn affectkinase activity. For example, the presence of the chemical entity mayincrease or decrease kinase activity by directly binding to the kinase,by causing (directly or indirectly) another factor to increase ordecrease the kinase activity, or by (directly or indirectly) increasingor decreasing the amount of kinase present in the cell or organism.

In certain embodiments, compounds described herein are modulators ofprotein kinases. In certain embodiments, the compounds described hereinare inhibitors of the protein kinases. In certain embodiments, thecompounds inhibit at least one kinase chosen from EphB₄, c-Kit, PDGFRβ,and VEGFR2 kinases. In certain embodiments, the compounds inhibit morethan one kinase chosen from EphB₄, c-Kit, PDGFRβ, and VEGFR2 kinases.

Accordingly, the invention includes a method of treating a patient, suchas a human patient, having a disease or disorder responsive to kinasemodulation, comprising administering to the patient a therapeuticallyeffective amount of at least one chemical entity described herein.

A method of treating a patient having a disease or disorder responsiveto kinase modulation, particularly VEGFR2 modulation, comprisingadministering to the patient a therapeutically effective amount of oneor more of the compounds of Formula I is provided.

Also provided is the use of at least one chemical entity describedherein for the manufacture of a medicament for the treatment of apatient having a disease or disorder responsive to kinase modulation,particularly VEGFR2 modulation. Also provided is the use of at least onechemical entity described herein for the manufacture of a medicament forthe treatment of a patient having angiogenesis.

In some embodiments, the chemical entities described herein inhibit atleast one kinase chosen from EphB₄, c-Kit, PDGFRβ, and VEGFR2 and can beuseful for the treatment of diseases and disorders responsive tomodulation of at least one of such kinases. In some embodiments, thedisease or disorder is characterized by angiogenesis supporting solidtumor growth or dysregulated local vascularization.

Methods of treatment also include modulating kinase activity, byinhibiting ATP binding or hydrolysis by a kinase or by some othermechanism, in vivo, in a patient suffering from a disease or disorderresponsive to kinase modulation, by administering a therapeuticallyeffective amount of at least one chemical entity described herein toinhibit kinase activity in vitro.

In some embodiments, the condition responsive to kinase modulation iscancer or a disease or disorder characterized by a change inangiogenesis.

The invention includes a method of treating a patient having cancer or adisease or disorder characterized by a change in angiogenesis byadministering at least one chemical entity described herein. Theinvention provides methods of treatment in which a compound of theinvention is the only active agent given to a patient and also includesmethods of treatment in which at least one chemical entity describedherein is given to a patient in combination with one or more additionalactive agents.

Certain compounds described herein can be useful for treating a patientsuffering from a disease or disorder responsive to kinase modulation.

In certain embodiments, the conditions, diseases and/or disorders thatare affected using compounds of Formula I and compositions comprisingsuch compounds include, but are not limited to, psoriasis, angiogenesis,cancer (for example, chronic myelogenous leukemia, gastrointestinalstromal tumors, non-small cell lung cancer, breast cancer, ovariancancer, recurrent ovarian cancer, prostate cancer such as hormonalrefractory prostate cancer, kidney cancer, head and neck cancer, orcolorectal cancer), immunoregulation (graft rejection), atherosclerosis,rheumatoid arthritis, Parkinson's disease, Alzheimer's disease, diabetes(for example insulin resistance or diabetic retinopathy), septic shock,and the like.

Because kinases play an active role in angiogenesis certain compoundsdescribed herein can be useful for modulating angiogenesis.Angiogenesis, the formation of new blood vessels from preexisting ones,plays a critical role in many pathological settings, including cancer,chronic inflammation, diabetic retinopathy and macular degeneration.Angiogenesis is regulated by multiple cell-signaling pathways, includingpathways controlled by cellular kinases. Blocking angiogenesis, throughthe modulation of cell kinases, therefore, can represent effectiveapproach to the treatment of diseases such as cancer. Thus methods oftreatment include administering a therapeutically effective amount of atleast one chemical entity described herein to treat these diseases ordisorders, e.g., to decrease the symptoms or slow the progression ofthese diseases or disorders by inhibiting the rate of angiogenesis in atissue.

The invention further includes methods for combination drug therapy, inwhich a compound of the invention is given to a patient together withone or more other active agents. Thus in one embodiment the inventionprovides a method of treating cancer, which comprises administering to apatient in need thereof an effective amount of at least one chemicalentity described herein together with a second active agent, which canbe useful for treating cancer. For example the second agent may be anantitumor agent. Treatment with the second active agent may be prior to,concomitant with, or following treatment with at least one chemicalentity described herein.

In certain embodiments, at least one chemical entity chosen fromcompounds of Formula 1, and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, and prodrugs thereof, is combined withat least one second active agent in a single dosage form.Radiotherapeutic anti-tumor agents may also be used alone or incombination with chemotherapeutic agents. Suitable anti-tumortherapeutics that may be used in combination with at least one chemicalentity described herein. Examples of anti-tumor therapeutics include, ingeneral, microtubule-stabilizing agents (such as paclitaxel (also knownas Taxol), docetaxel (also known as Taxotere), epothilone A, epothiloneB, desoxyepothilone A, desoxyepothilone B or their derivatives);microtubule-disruptor agents; alkylating agents, anti-metabolites;epidophyllotoxin; an antineoplastic enzyme; a topoisomerase inhibitor;procarbazine; mitoxantrone; platinum coordination complexes; biologicalresponse modifiers and growth inhibitors; hormonal/anti-hormonaltherapeutic agents and haematopoietic growth factors.

Exemplary classes of anti-tumor therapeutics include, for example, theanthracycline family of drugs, the vinca drugs, the mitomycins, thebleomycins, the cytotoxic nucleosides, the taxanes, the epothilones,discodermolide, the pteridine family of drugs, diynenes and thepodophyllotoxins. Particularly useful members of those classes include,for example, doxorubicin, carminomycin, daunorubicin, aminopterin,methotrexate, methopterin, dichloro-methotrexate, mitomycin C,porfiromycin, herceptin, 5-fluorouracil, 6-mercaptopurine, gemcitabine,cytosine arabinoside, podophyllotoxin or podo-phyllotoxin derivativessuch as etoposide, etoposide phosphate or teniposide, melphalan,vinblastine, vincristine, leurosidine, vindesine, leurosine, paclitaxeland the like. Other useful antineoplastic agents include estramustine,cisplatin, carboplatin, cyclophosphamide, bleomycin, tamoxifen,ifosamide, melphalan, hexamethyl melamine, thiotepa, cytarabin,idatrexate, trimetrexate, dacarbazine, L-asparaginase, camptothecin,CPT-11, topotecan, ara-C, bicalutamide, flutamide, leuprolide,pyridobenzoindole derivatives, interferons and interleukins.

In certain embodiments, at least one chemical entity chosen fromcompounds of Formula 1, and pharmaceutically acceptable salts, solvates,chelates, non-covalent complexes, and prodrugs thereof, can beadministered in combination with an anti-inflammatory agent.Anti-inflammatory agents include NSAIDs, non-specific and COX-2 specificcyclooxgenase enzyme inhibitors, gold-containing compounds,corticosteroids, methotrexate, tumor necrosis factor receptor (TNF)receptors antagonists, immunosuppressants and methotrexate. Examples ofNSAIDs include ibuprofen, flurbiprofen, naproxen and naproxen sodium,diclofenac, combinations of diclofenac sodium and misoprostol, sulindac,oxaprozin, diflunisal, piroxicam, indomethacin, etodolac, fenoprofencalcium, ketoprofen, sodium nabumetone, sulfasalazine, tolmetin sodium,and hydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors (i.e., a compound that inhibits COX-2 with an IC₅₀ that is atleast 50-fold lower than the IC₅₀ for COX-1) such as celecoxib,valdecoxib, lumiracoxib, etoricoxib and/or rofecoxib. In certainembodiments, the anti-inflammatory agent can be a salicylate.Salicylates include acetylsalicylic acid or aspirin, sodium salicylate,and choline and magnesium salicylates. The anti-inflammatory agent canalso be a corticosteroid. For example, the corticosteroid may becortisone, dexamethasone, methylprednisolone, prednisolone, prednisolonesodium phosphate, and prednisone. In certain embodiments, theanti-inflammatory agent can be a gold-containing compound such as gold,sodium thiomalate or auranofin. In certain embodiments, theanti-inflammatory agent can be a metabolic inhibitor such as adihydrofolate reductase inhibitor, such as methotrexate or adihydroorotate dehydrogenase inhibitor, such as leflunomide. Certainembodiments of the present disclosure include combinations in which atleast one anti-inflammatory compound can be an anti-C5 monoclonalantibody (such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody, and combinations in which at least one active agent is animmunosuppressant compound such as methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, or mycophenolate mofetil.

Dosage levels of the order of from 0.1 mg to 140 mg per kilogram, suchas 1 to 50 mg per kilogram, of body weight per day can be useful in thetreatment of the above-indicated conditions (0.5 mg to 7 g per patientper day). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain from 1 mg to 500 mg of an activeingredient.

Frequency of dosage may also vary depending on the compound used and theparticular disease treated. In certain embodiments, a dosage regimen of4 times daily or less is used. In certain embodiments, a dosage regimenof 1 or 2 times daily is used.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease in the patient undergoing therapy.

EXAMPLES

The invention is further illustrated by the following non-limitingexamples.

In the examples below, the following abbreviations have the followingmeanings. If an abbreviation is not defined, it has its generallyaccepted meaning.

DME = dimethyl ether DMEM = Dulbecco's modified Eagle's medium DMF =N,N-dimethylformamide DMSO = dimethylsulfoxide g = gram h = hour mg =milligram min = minutes mL = milliliter mmol = millimoles mM =millimolar ng = nanogram nm = nanometer nM = nanomolar PBS = phosphatebuffered saline μL = microliter μM = micromolar

Example 1

Compound 1a was prepared using the procedure described in Org. Lett.2003, 5, 5023.

4-Bromo-1-pyridin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridine (1b)

A 250-mL argon-purged round-bottomed flask equipped with a magneticstirrer is charged with 4-Bromo-1H-pyrrolo[2,3-b]pyridine (0.70 g, 3.55mmol) and DMF (25 mL) and the solution is cooled to −15° C. A 60%dispersion of sodium hydride in mineral oil (183 mg, 4.58 mmol) is thenadded and the reaction stirred at −15° C. for 25 min. The reaction isthen charged with 4-picolylchloride hydrochloride (376 mg, 2.29 mmol)and stirred at −15° C. for a further 5 min. After such time the coolingbath is removed and the reaction is stirred for 30 min at ambienttemperature. Additional 4-picolylchloride hydrochloride (117 mg, 0.71mmol) and a 60% dispersion of sodium hydride in mineral oil (28 mg, 0.71mmol) are then added and the reaction is stirred at ambient temperaturefor a further 30 min. The reaction is then poured into ethyl acetate(100 mL) and the mixture is washed with 3% aqueous sodium bicarbonate(1×100 mL), water (2×100 mL) and brine (1×100 mL). The organic layer isseparated, dried over sodium sulfate and concentrated in vacuo toprovide a residue, which is then purified by flash chromatography toafford 1b as a yellow solid.

N-(dipheylmethylene)-1-(pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4-amine(1c)

A 25-mL round-bottomed flask equipped with magnetic stirrer and refluxcondenser is charged with rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl(0.040 g, 0.063 mmol), Pd₂dba₃ (0.019 g, 0.021 mmol) and sodiumtert-butoxide (0.282 g, 2.94 mmol). The reaction vessel is then purgedwith a stream of nitrogen for 0.5 h. After such time, a solution ofCompound 1b (0.600 g, 2.10 mmol) in toluene (6 mL) followed bybenzophenone imine (0.45 g, 2.51 mmol) is added. The reaction is thenheated at reflux for 2 h. After such time the reaction is cooled to roomtemperature and concentrated under reduced pressure. The resulting oilis then purified by column chromatography to afford Compound 1c as ayellow oil.

1-(Pyridin-4-yl)methyl-1H-pyrrolo[2,3-b]pyridin-4-ylamine (1d)

A 25-mL round-bottomed flask equipped with magnetic stirrer is chargedwith Compound 1c (0.580 g, 1.49 mmol), THF (10 mL) and 2N hydrochloricacid (2.0 mL). The reaction is then stirred at room temperature for 1 h.After such time, the reaction is partitioned between ethyl acetate (15mL) and water (15 mL). The aqueous layer is separated and washed withethyl acetate (2×25 mL). After basifying to pH 9 with solid potassiumcarbonate in order to liberate the free base of Compound 1d, the aqueouslayer is extracted with ethyl acetate (2×25 mL). The extracts are thencombined and dried over sodium sulfate. The sodium sulfate is removed byfiltration and the filtrate concentrated under reduced pressure. Theresulting residue is then purified by column chromatography to affordCompound 1d as a white solid.

1-(5-Bromo-2-methoxy-phenyl)-3-(1-pyridin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-urea(1e)

To a solution of Compound 1d (50 mg, 0.2 mmol) indichloromethane:dimethylformamide (4.0 mL, 3:1) is added4-bromo-2-isocyanato-1-methoxy-benzene (50 mg, 0.2 mmol, 1 equiv.) andthe reaction mixture is heated for 16 hrs, the solvent is then removedand the residue is purified using flash chromatography to affordCompound 1e as a white solid.

1-(5-Chloro-2-methoxy-phenyl)-3-(1-pyridin-4-ylmethyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-urea(1f)

Compound 1d (52 mg, 0.233 mmol) is dissolved in dichloromethane (5.0 mL)and 4-bromo-2-isocyanato-1-methoxy-benzene (1.0 equiv., 44 mg, 0.233mmol) is then added and stirred at room temperature for 3 hours undernitrogen atmosphere. All solvent is then removed by rotary evaporationand the crude product is purified via preparative TLC to afford Compound1f as an off-white solid.

Example 2

The following compounds were prepared using procedures similar to thosedescribed above. Those of ordinary skill in the art of organic synthesiswill recognize when starting materials or reaction conditions should bevaried to obtain the desired compound.

MS data reported in this example was obtained as follows:

MS conditions: Electrospray MS is performed on a MICROMASS LCT equippedwith a LockSpray source for accurate mass measurements. Spectra areacquired in positive ion mode from 100-1000 Da at an acquisition rate of1 spectrum/0.9 s with a 0.1 s interscan delay. The instrument is tunedfor a resolution of 5000 (FWHM). Every 5^(th) scan is taken from thereference position of the Lockspray source. Leucine enkephalin (556.2771[M+H]⁺) is used as the reference, or lock mass.

MS m/z Structure Name/MW (M + H)

1-(5-bromo-2- methoxyphenyl)-3-(1- (pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)urea C₂₁H₁₈BrN₅O₂ 451.06 452.24

1-(5-chloro-2- methoxyphenyl)-3-(1- (pyridin-4-ylmethyl)-1H-pyrrolo[2,3-b]pyridin-4- yl)urea C₂₁H₁₈ClN₅O₂ 407.11 408.22

Example 3

5-Methyl-4-nitro-1H-benzoimidazole (2b)

A 500-mL single-neck round-bottomed flask equipped with a magneticstirrer was charged with compound 2a (7.45 g, 56.4 mmol) and 98%sulfuric acid (50 mL). The mixture was then cooled to 0° C. and treatedportionwise with potassium nitrate (5.72 g, 56.5 mmol) over 15 minutes.Once the last addition was complete, the reaction was stirred for 1 h at0° C. The ice bath was then removed and stirring continued at ambienttemperature for 14 h. After this time the reaction was cooled to 0° C.and basified to pH 10 by the slow addition of 29% ammonium hydroxide(300 mL). The resulting suspension was filtered and the precipitatewashed with water (3×100 mL). The filtrate was then extracted with ethylacetate (3×100 mL) and the combined organic layers dried over sodiumsulfate, filtered and concentrated under reduced pressure. The resultingresidue and the above precipitate were combined and dried under reducedpressure at 50° C. Purification of this material by flash chromatographyafforded compound 2b as a light yellow solid.

5-Methyl-4-nitro-1-(pyridin-4-yl)methyl-1H-benzimidazole (2c)

A 200-mL round-bottomed flask equipped with a magnetic stirrer wascharged with 4-picolylchloride hydrochloride (1.20 g, 7.34 mmol) and DMF(30 mL) under argon. A 60% dispersion of sodium hydride in mineral oil(294 mg, 7.34 mmol) was added to the resulting solution and the reactionstirred at room temperature for 5 min. The reaction was then chargedwith potassium carbonate (3.55 g, 25.7 mmol), stirred at roomtemperature for 5 min and compound 2b (1.30 g, 7.34 mmol) was added.Once this addition was complete, the reaction was stirred at roomtemperature for 19 h. After this time the reaction was poured into ethylacetate (1 L) and the resulting mixture washed with water (3×750 mL)followed by brine (750 mL). The resulting organic layer was dried oversodium sulfate, then filtered and the filtrate concentrated underreduced pressure providing a residue, which was purified by flashchromatography to afford compound 2c as a light-yellow solid.

5-Methyl-1-(pyridin-4-yl)methyl-1H-benzimidazol-4-ylamine (2d)

A 200-mL round-bottomed flask equipped with mechanical stirrer wascharged with 5-Methyl-4-nitro-1-(pyridin-4-yl)methyl-1H-benzimidazole(881 mg, 3.46 mmol), iron powder (−325 mesh, 3.87 g, 6.92 mmol) andacetic acid (50 mL), and the resulting mixture stirred at 50° C. for 15min. After this time the reaction was cooled to room temperature,diluted with 1:1 methylene chloride/methanol (1 L) and filtered througha pad of Celite 521. After washing the filter cake with 1:1 methylenechloride/methanol (2×50 mL), the filtrate was concentrated in vacuo. Theresulting residue was dissolved in methylene chloride (50 mL) andvigorously stirred with 1M aqueous sodium hydroxide (50 mL). Theresulting emulsion was filtered through a pad of Celite 521, the padwashed with methylene chloride (2×25 mL) and the organic layer of thefiltrate separated and dried over sodium sulfate. Removal of the dryingagent by filtration, followed by evaporation of the filtrate in vacuogave a residue which was purified by flash chromatography. This purifiedmaterial was dissolved in warm methylene chloride (15 mL) and thesolution diluted with hexanes (35 mL). The resulting precipitate wasfiltered, washed with hexanes (3×100 mL) and dried under reducedpressure for 1.5 h to afford compound 2d as an off-white solid.

1-(5-Bromo-2-methoxy-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2e)

Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask anddissolved in dichloromethane (3 mL).2-Isocyanato-1-methoxy-4-trifluoromethyl-benzene (90 mg, 0.42 mmol) isadded as a solid and the homogeneous mixture is stirred for 4 h. Theprecipitate is collected via filtration and the solids are washed withether and collected to yield compound 2e as a white amorphous solid.

1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2f)

Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask anddissolved in dichloromethane (3 mL).4-Bromo-2-isocyanato-1-methoxy-benzene (96 mg, 0.42 mmol) is added as asolid and the homogeneous mixture is stirred for 4 h. The precipitate iscollected via filtration and are washed with ether and collected toyield the title compound as a white amorphous solid.

1-(4-Chloro-3-trifluoromethyl-phenyl)-3-(5-methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2g)

Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask anddissolved in dichloromethane (3 mL).1-Chloro-4-isocyanato-2-trifluoromethyl-benzene (93 mg, 0.42 mmol) isadded as a solid and the homogeneous mixture is stirred for 4 h. Theprecipitate is collected via filtration and are washed with ether andcollected to yield compound 2g as a white amorphous solid.

1-(5-Methyl-1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-3-(4-methyl-3-trifluoromethyl-phenyl)-urea(2h)

Compound 2d (100 mg, 0.42 mmol) is weighed into a round bottom flask anddissolved in dichloromethane (3 mL).4-Isocyanato-1-methyl-2-trifluoromethyl-benzene (85 mg, 0.42 mmol) isadded as a solid and the homogeneous mixture is stirred for 4 h. Theprecipitate is collected via filtration and the solids are washed withether and collected to yield compound 2h as a white amorphous solid.

Example 4

4-Nitro-1H-benzimidazole (3b)

A 500-mL round-bottomed flask equipped with a magnetic stirrer andreflux condenser was charged with compound 3a (4.70 g, 30.6 mmol),toluene (200 mL), triethyl orthoformate (13.6 g, 92.0 mmol) andp-toluenesulfonic acid (386 mg, 1.5 mmol) and the mixture then heated toreflux under nitrogen. After 1.5 h the reaction was cooled to 0° C. andthe resulting precipitate filtered, washed with ether (3×50 mL) anddried in the vacuum oven to afford compound 3b as a tan powder.

4-Nitro-1-(pyridin-4-yl)methyl-1H-benzimidazole (3c)

A 500-mL round-bottomed flask equipped with a magnetic stirrer andnitrogen inlet is charged with compound 3b (3.30 g, 30.6 mmol),potassium carbonate (8.95 g, 64.8 mmol), anhydrous DMF (200 mL) and4-chloromethylpyridine hydrochloride (3.98 g, 24.3 mmol) and the mixtureis then stirred under nitrogen for 24 h at ambient temperature. Aftersuch time the reaction is partitioned between water (200 mL) and ethylacetate (200 mL). The aqueous layer is separated and extracted withethyl acetate (6×250 mL). The combined organic extracts are dried withsodium sulfate, and the drying agent is filtered off. The filtrate isthen concentrated under vacuum to give a brown solid, which is purifiedby column chromatography to afford compound 3c as a yellow solid.

1-(Pyridin-4-yl)methyl-1H-benzimidazol-4-ylamine (3d)

Using the same general procedure as described above for the preparationof 5-methyl-1-(pyridin-4-yl)methyl-1H-benzimidazol-4-ylamine (2d),reduction of 4-nitro-(1-pyridin-4-yl)methyl-1H-benzimidazole 3c (1.71 g)gave 3d as a pale yellow powder.

1-(5-Bromo-2-methoxy-phenyl)-3-(1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea

Compound 3d (75 mg, 0.334 mmol) is dissolved indimethylformamide/dichloromethane (1:4, 5.0 mL) and4-bromo-2-isocyanato-1-methoxy-benzene (1.0 equiv., 76 mg, 0.334 mmol)is added at room temperature and allowed to react for 16 hours undernitrogen atmosphere. All solvent is then removed on a rotary evaporatorand toluene (3×25 mL) is added and stripped off to remove residualdimethylformamide. The crude solid is then triturated using ethyl ether,and the resulting solid is then filtered and dried yielding compound 2ias a white solid.

1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-(1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2j)

Compound 3d (75 mg, 0.334 mmol) is dissolved indimethylformamide/dichloromethane (1:4, 5.0 mL) and2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (1.0 equiv., 73 mg,0.334 mmol) is added at room temperature and allowed to react for 16hours under nitrogen atmosphere. All solvent is then removed on a rotaryevaporator and toluene (3×25 mL) is added and stripped off to removeresidual dimethylformamide. The crude solid is then triturated usingethyl ether, and the resulting solid is then filtered and dried yieldingtitle compound as a white solid.

Example 5

Compound 6 may be synthesized as illustrated by methods described inU.S. Pat. No. 5,212,182.

4-(4-Nitro-benzoimidazol-1-ylmethyl)-quinoline (4a)

Compound 4a was synthesized in the same manner as compound 3c using4-chloromethylquinoline hydrochloride instead of 4-chloromethylpyridinehydrochloride.

1-Quinolin-4-ylmethyl-1H-benzoimidazol-4-ylamine (4b)

Compound 4b was synthesized in the same manner as compound 3d.

Example 6

4-(5-Methyl-4-nitro-benzoimidazol-1-ylmethyl)-quinoline (5a)

Compound 5a was synthesized in the same manner as compound 2c using4-chloromethylquinoline hydrochloride instead of 4-chloromethylpyridinehydrochloride.

5-Methyl-1-quinolin-4-ylmethyl-1H-benzoimidazol-4-ylamine (5b)

Compound 5b was synthesized in the same manner as compound 2d.

1-(5-Bromo-2-methoxy-phenyl)-3-(1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2k)

To solution of compound 4b (50 mg, 0.2 mmol) in dichloromethane (3.0 mL)is added 0.04 g (0.2 mmol, 1 eq.) of4-bromo-2-isocyanato-1-methoxy-benzene (40 mg, 0.2 mmol, 1 equiv.) andthe resulting reaction mixture is heated to 40° C. for 2 hrs, then iscooled to room temperature and treated with ethyl ether. The precipitateis filtered and collected to give compound 2k as a white powder.

1-(5-Bromo-2-methoxy-phenyl)-3-(5-methyl-1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea(2l)

To solution of compound 5b (50 mg, 0.2 mmol) in dichloromethane (3.0 mL)is added (40 mg, 0.2 mmol, 1 equiv.) of4-bromo-2-isocyanato-1-methoxy-benzene and the resulting reactionmixture is heated to 40° C. for 2 hrs, then is cooled to roomtemperature and treated with ethyl ether. The precipitate was filteredand collected to give compound 21 as a white powder.

Example 7

The following compounds were prepared using procedures similar to thosedescribed in Examples 3 to 6. Those of ordinary skill in the art oforganic synthesis will recognize when starting materials or reactionconditions should be varied to obtain the desired compound.

MS data reported in this example was obtained as follows:

MS conditions: Electrospray MS is performed on a MICROMASS LCT equippedwith a LockSpray source for accurate mass measurements. Spectra areacquired in positive ion mode from 100-1000 Da at an acquisition rate of1 spectrum/0.9 s with a 0.1 s interscan delay. The instrument is tunedfor a resolution of 5000 (FWHM). Every 5^(th) scan is taken from thereference position of the Lockspray source. Leucine enkephalin (556.2771[M+H]⁺) is used as the reference, or lock mass.

Structure Name/MW M+

1-(5-Bromo-2-methoxy- phenyl)-3-(1-pyridin-4- ylmethyl-1H-benzoimidazol-4-yl)- urea 451.06 452.17

1-(2-Methoxy-5- trifluoromethyl-phenyl)- 3-(1-pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)- urea 441.14 442.20

1-(5-Bromo-2-methoxy- phenyl)-3-(1-quinolin-4- ylmethyl-1H-benzoimidazol-4-yl)- urea 501.08 502.03

1-(5-Bromo-2-methoxy- phenyl)-3-(5-methyl-1- quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)- urea 515.10 516.00

1-(5-Bromo-2-methoxy- phenyl)-3-(5-methyl-1- pyridin-4-ylmethyl-1H-benzoimidazol-4-yl)- urea 455.16 456.05

1-(2-Methoxy-5- trifluoromethyl-phenyl)- 3-(5-methyl-1-pyridin-4-ylmethyl-1H- benzoimidazol-4-yl)- urea 465.08 466.04

1-(4-Chloro-3- trifluoromethyl-phenyl)- 3-(5-methyl-1-pyridin-4-ylmethyl-1H- benzoimidazol-4-yl)- urea 459.11 460.18

1-(5-Methyl-1-pyridin-4- ylmethyl-1H- benzoimidazol-4-yl)-3-(4-methyl-3- trifluoromethyl-phenyl)- urea 439.16 440.26

Example 8 Assay for EphB₄ Kinase Activity

The following is a procedure for a standard biochemical assay for EphB₄Kinase Activity that can be used to test compounds disclosed in thisapplication.

Materials:

96-well, ½ area flat bottom, white polystyrene plates are purchased fromCostar, cat #3693.

The cytoplasmic domain of recombinant EphB₄ kinase (amino acids 596-987,Homo sapiens EphB₄, GENBANK Accession No. AY056047.1) with a C-terminalV5-(his)₆ tag is purified from Sf9 cells. Purity of >95% is assessed bySypro-Ruby staining of SDS gels.

PTK Biotinylated Peptide Substrate 2, is purchased from Promega, cat#V288A.

LANCE Eu-W1024 labeled anti-phosphotyrosine antibody (PT66) is purchasedfrom Perkin-Elmer, cat #AD0068. Kinase Buffer is purchased from CellSignaling, cat #9802.

Dilutions of compounds are made in 100% DMSO at 20× the final desiredconcentration. Compounds in 100% DMSO are transferred (1.25 μL) to the96 well assay plate. A 18.75 μL volume of master mix containing thefinal concentrations (in 25 ul) of 0.01% BSA, 1× Cell Signaling KinaseBuffer, 0.5 μM PTK Biotinylated Peptide Substrate 2, and 18.6 ng/wellng/well of EphB₄ kinase is added to all wells, except the four negativecontrol wells (which contain no kinase), and mixed. To initiate thereaction, 5 μL of 550 uM ATP is added to each well. (Final Concentrationof ATP=110 μM). The reactions are incubated for 1 hour at roomtemperature (RT). After incubation a quantity of 8.35 μL of a 4×SA-APCDetection Mix is added to each well. The final concentration ofEu-labelled PT66 antibody is 1 nM and the SA-APC is 20 nM (based on theSA moiety). The reaction plates are incubated at RT for at least 15minutes after SA-APC Detection Mix addition. The reaction plates areread on an Envision plate reader (Perkin-Elmer) with 605 nm Excitationat 605 nm and 640 nm Emission wavelengths. Values are corrected for thefluorescence in the absence of enzyme and inhibition curves are fit tothe data using a Logit curve-fitting algorithm. IC₅₀ values aredetermined from these inhibition curves.

Example 9 EphB4 Cellular Assay

The following is a procedure for a standard cell-based assay for EphB₄kinase activity that can be used to test compounds disclosed in thisapplication.

HEK293 cells stably expressing V5-epitope tagged EphB₄ are grown to ˜75%confluency, and then incubated for 90 min at 37° C. in low serum media(Optimem) containing test compound. Cells are stimulated for 10 minutesat 37° C. with 500 ng/ml EphrinB₂/Fc chimera and 50 ng/mlgoat-anti-human IgG (FC-specific) in low serum media containing testcompound. Cells are washed in ice-cold PBS, lysed, and protein assaysare performed on the cleared lysates. Equal protein amounts of eachsample are subjected to SDS-PAGE and western blotting with either ananti-phosphotyrosine antibody or an anti-V5 antibody to control fortotal amounts of V5-epitope-tagged EphB₄ in each lysate.

Example 10 Biochemical Assay S

The following is a procedure for a standard biochemical assay that canbe used to test activity of compounds disclosed herein as inhibitors ofc-Kit, PDGFRβ, and VEGFR2, kinase activity.

Test compounds are diluted 1:20 from an original 200 μM DMSO stock andincubated with recombinant c-Kit (10 ng), or VEGFR2 (1 ng) enzyme(ProQinase GmbH, Germany), biotinylated peptide (PTK peptide 2, Promega)in Cell Signalling kinase buffer (c-Kit) or Upstate Kinase buffer(VEGFR2) and 5 ul of ATP (final concentrations: 85 μM for the VEGFR2assay and 150 μM for the c-Kit assay) for 60 minutes at roomtemperature. For PDGFRβ, test compounds are diluted 1:20 from anoriginal 200 μM DMSO stock and incubated with recombinant PDGFRβ (2 ng)(ProQinase GmbH, Germany), biotinylated peptide (PTK peptide 2,Promega), 1 μM poly-L-lysine (Sigma) in Upstate Kinase buffer and 5 μlof ATP (final concentration: 2.5 μM) for at least 15 minutes at roomtemperature. The final assay volume is 25 μl. After incubation adetection Mix, which includes 1 nM LANCE Eu-W1024 labeledanti-phosphotyrosine antibody PT66 (Perkin-Elmer, cat #AD0068) and 20 nMSA-APC (based on the SA moiety), is added. The reaction plates areincubated at room temperature for at least 15 minutes after SA-APCdetection mix addition. The reaction plates are then read on an Envisionplate reader (Perkin-Elmer) with 605 nm excitation 615 nM and 640 nmemission wavelengths.

For a negative control, i.e. a readout in which the kinases are notinhibited, the assay is run without any test compound added.Staurosporine, a general kinase inhibitor, is used as a positivecontrol.

IC₅₀ values are determined from an 11-point saturation binding curve fortest compounds that show significant inhibition of one of the tyrosinekinases. In these assays concentration of test compound ranges from 10μM to 20 nM. Equilibrium binding parameters are determined by fittingthe allosteric Hill equation to the measured values with the aid of thecomputer program, such as FitP™ (BIOSOFT, Ferguson, Mo.).

Example 11 Test Results

Certain compounds described in Examples 2 and 7 were tested in theassays for EphB₄ kinase activity (as outlined in Examples 8 and 9), andfound to exhibit an IC₅₀ of 1 micromolar or less. Certain of thosecompounds exhibited an IC₅₀ of 500 nM or less in these assays.

Certain compounds of Examples 2 and 7 were tested in the assay forPDGFRβ kinase activity (as outlined in example 10), and found to exhibitan IC₅₀ of 1 micromolar or less. Certain of those compounds exhibited anIC₅₀ of 500 nM or less in the assay for PDGFRβ kinase activity.

Certain compounds described in Examples 2 and 7 were tested in the assayfor c-Kit kinase activity (as outlined in example 10) and found toexhibit an IC₅₀ of 1 micromolar or less. Certain of those compoundsexhibited an IC₅₀ of 500 nM or less in the assay for c-Kit kinaseactivity. Certain of those compounds exhibited an IC₅₀ of 50 nM or lessin this assay.

Certain compounds described in Examples 2 and 7 were also tested in theassay for VEGFR2 kinase activity (as outlined in example 10). Certain ofthose compounds were found to exhibit an IC₅₀ of 1 micromolar or less.Certain of those compounds exhibited an IC₅₀ of 100 nM or less in thisassay. Certain of those compounds exhibited an IC₅₀ of 50 nM or less inthis assay.

Certain compounds described in Examples 2 and 7 were also tested in theassays described herein and were found to exhibit an IC₅₀ of 1micromolar or less against two or more kinases chosen from EphB₄,PDGFRβ, c-Kit, and VEGFR2. Certain compounds described in Examples 2 and7 were also tested in the assays described herein and were found toexhibit an IC₅₀ of 100 nm or less against two or more kinases chosenfrom EphB₄, PDGFRβ, c-Kit, and VEGFR2.

Certain compounds described in Examples 2 and 7 were also tested in theassays described herein and were found to exhibit an IC₅₀ of 1micromolar or less against three or more kinases chosen from EphB₄,PDGFRβ, c-Kit, and VEGFR2. Certain compounds described in Examples 2 and7 were also tested in the assays described herein and were found toexhibit an IC₅₀ of 100 nm or less against three or more kinases chosenfrom EphB₄, PDGFRβ, c-Kit, and VEGFR2.

Certain compounds described in Examples 2 and 7 were also tested in theassays described herein and were found to exhibit an IC₅₀ of 1micromolar or less against each of EphB₄, PDGFRβ, c-Kit, and VEGFR2.Certain compounds described in Examples 2 and 7 were also tested in theassays described herein and were found to exhibit an IC₅₀ of 100 nm orless against each of EphB₄, PDGFRβ, c-Kit, and VEGFR2.

While certain embodiments have been shown and described, variousmodifications and substitutions may be made thereto without departingfrom the spirit and scope of the invention. Accordingly, it is to beunderstood that the present invention has been described by way ofillustration and not limitations.

1. At least one chemical entity chosen from compounds of Formula 3

and pharmaceutically acceptable salts thereof, wherein U, V, and W areCH; R represents 0 to 2 substituents independently chosen from hydroxy,nitro, cyano, optionally substituted amino, aminocarbonyl, halo,carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, sulfanyl, sulfinyl, sulfonyl, optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocycloalkyl; R₁ is optionally substitutedquinolin-4-yl; Z₁ is —CR₅R₆— wherein each R₅ and R₆ is independentlychosen from hydrogen, optionally substituted C₁-C₆ alkyl, and halo; andm is chosen from 0, 1, and 2; R₂ is optionally substituted aryl; and R₃and R₄ are each independently chosen from hydrogen, optionallysubstituted C₁-C₆ alkyl, optionally substituted aryl, and optionallysubstituted heteroaryl.
 2. At least one chemical entity of claim 1wherein at least one of R₅ and R₆ is hydrogen.
 3. At least one chemicalentity of claim 2 wherein both of R₅ and R₆ are hydrogen.
 4. At leastone chemical entity of claim 1 wherein m is 1 and at least one of R₅ andR₆ is hydrogen.
 5. At least one chemical entity of claim 4 wherein bothof R₅ and R₆ are hydrogen.
 6. At least one chemical entity of claim 1wherein m is
 0. 7. At least one chemical entity of claim 1 wherein R₂ ischosen from phenyl, substituted phenyl,

wherein A is chosen from CH₂ and O, D is chosen from CH and N, the wavyline represents the attachment point of R₂ to the urea group of Formula1, and R₉ is chosen from hydroxy, nitro, cyano, optionally substitutedamino, aminocarbonyl, halo, carboxy, optionally substituted acyl,optionally substituted alkoxycarbonyl, optionally substituted C₁-C₆alkyl, optionally substituted C₁-C₆ alkoxy, optionally substitutedaryloxy, sulfanyl, sulfinyl, sulfonyl, optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocycloalkyl.
 8. At least one chemical entity of claim 7 wherein R₂is chosen from phenyl and substituted phenyl wherein substituted phenylis chosen from mono-, di-, and tri-substituted phenyls and whereinsubstituents on the substituted phenyl are independently chosen fromhydroxy, nitro, cyano, optionally substituted amino, aminocarbonyl,halo, carboxy, optionally substituted acyl, optionally substitutedalkoxycarbonyl, optionally substituted C₁-C₆ alkyl, optionallysubstituted C₁-C₆ alkoxy, optionally substituted aryloxy, sulfanyl,sulfinyl, sulfonyl, optionally substituted aryl, optionally substitutedheteroaryl, and optionally substituted heterocycloalkyl.
 9. At least onechemical entity of claim 8 wherein the substituents on the substitutedphenyl are independently chosen from hydroxy, nitro, cyano, optionallysubstituted amino, halo, carboxy, optionally substituted C₁-C₆ alkyl,optionally substituted C₁-C₆ alkoxy, optionally substituted phenoxy,C₁-C₆ alkylsulfanyl, C₁-C₆ acyl, C₁-C₆ alkoxycarbonyl, optionallysubstituted heteroaryl, and optionally substituted heterocycloalkyl. 10.At least one chemical entity of claim 9 wherein the substituents on thesubstituted phenyl are independently chosen from hydroxy, cyano, halo,optionally substituted C₁-C₂ alkyl, phenoxy, and optionally substitutedC₁-C₂ alkoxy.
 11. At least one chemical entity of claim 10 wherein thesubstituents on the substituted phenyl are independently chosen fromhalo, methyl, methoxy, ethoxy, and trifluoromethyl.
 12. At least onechemical entity of claim 1 wherein R represents 1 or 2 substituentsindependently chosen from halo, C₁-C₂ alkyl, and C₁-C₂alkoxy.
 13. Atleast one chemical entity of claim 12 wherein R represents 1 or 2substituents independently chosen from halo, methyl, and methoxy.
 14. Atleast one chemical entity of claim 13 wherein R represents a substituentchosen from halo, methyl, and methoxy.
 15. At least one chemical entityof claim 1 wherein R is absent.
 16. At least one chemical entity ofclaim 1 wherein R₃ and R₄ are each independently chosen from hydrogenand methyl.
 17. At least one chemical entity of claim 16 wherein R₃ andR₄ are hydrogen.
 18. At least one chemical entity according to claim 1,wherein the at least one chemical entity exhibits an IC₅₀ of 1micromolar or less in a standard in vitro assay of EphB₄ kinaseactivity.
 19. At least one chemical entity according to claim 18,wherein the at least one chemical entity exhibits an IC₅₀ of 500nanomolar or less in a standard in vitro assay of EphB₄ kinase activity.20. At least one chemical entity according to claim 1, wherein the atleast one chemical entity exhibits an IC₅₀ of 1 micromolar or less in astandard in vitro assay of PDGFRβ kinase activity.
 21. At least onechemical entity according to claim 20, wherein the at least one chemicalentity exhibits an IC₅₀ of 500 nanomolar or less in a standard in vitroassay of PDGFRβ kinase activity.
 22. At least one chemical entityaccording to claim 1, wherein the at least one chemical entity exhibitsan IC₅₀ of 1 micromolar or less in a standard in vitro assay of c-Kitkinase activity.
 23. At least one chemical entity according to claim 22,wherein the at least one chemical entity exhibits an IC₅₀ of 500nanomolar or less in a standard in vitro assay of c-Kit kinase activity.24. At least one chemical entity according to claim 23, wherein the atleast one chemical entity exhibits an IC₅₀ of 50 nanomolar or less in astandard in vitro assay of c-Kit kinase activity.
 25. At least onechemical entity according to claim 1, wherein the at least one chemicalentity exhibits an IC₅₀ of 1 micromolar or less in a standard in vitroassay of VEGFR2 kinase activity.
 26. At least one chemical entityaccording to claim 25 wherein the at least one chemical entity exhibitsan IC₅₀ of 500 nM or less in a standard in vitro assay of VEGFR2 kinaseactivity.
 27. At least one chemical entity according to claim 26 whereinthe at least one chemical entity exhibits an IC₅₀ of 50 nM or less in astandard in vitro assay of VEGFR2 kinase activity.
 28. At least onechemical entity of claim 1 wherein the compound of Formula 3 is chosenfrom1-(5-Bromo-2-methoxy-phenyl)-3-(1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea;1-(5-Bromo-2-methoxy-phenyl)-3-(5-methyl-1-quinolin-4-ylmethyl-1H-benzoimidazol-4-yl)-urea.29. A pharmaceutical composition, comprising at least one chemicalentity of claim 1, together with at least one pharmaceuticallyacceptable vehicle chosen from carriers, adjuvants, and excipients. 30.A pharmaceutical composition of claim 29, wherein the composition isformulated in a form chosen from injectable fluids, aerosols, creams,gels, tablets, pills, capsules, syrups, ophthalmic solutions, andtransdermal patches.